Oral compositions for calculus retardation

ABSTRACT

ORAL COMPOSITIONS, SUCH AS TOOTHPASTE, MOUTHWASH, AND THE LIKE, CONTAINING CERTAIN CARBOXYPHOSPHONATES AS HEREIN DEFINED WHICH RETARD DENTAL CALCULUS FORMATION WITHOUT DAMAGING TOOTH STRUCTURE.

Int. Cl. A61k 7/16 US. Cl. 424-49 8 Claims ABSTRACT OF THE DISCLOSURE Oral compositions, such as toothpaste, mouthwash, and the like, containing certain carboxyphosphonates as herein defined which retard dental calculus formation without damaging tooth structure.

BACKGROUND OF THE INVENTION The field of this invention is oral compositions which term is used herein to designate products which in the ordinary course of usage are retained in the oral cavity for a time suflicient to contact substantially all of the dental surfaces, but are not intentionally ingested. Such products include, for example, dentrifices, mouthwashes, prophylaxis pastes and topical solutions.

Dental calculus, or tartar as it is sometimes called, is a deposit which forms on the surfaces of the teeth at the gingival margin. Supragingival calculus appears principally in the areas near the orifices of the salivary ducts; e.g., on the lingual surfaces of the lower anterior teeth and on the buccal surfaces of the upper first and second molars, and on the distal surfaces of the posterior molars.

Mature calculus consists of an inorganic portion which is largely calcium phosphate arranged in a hydroxylapatite crystal lattice structure similar to bone, enamel and dentine. An organic portion is also present and consists of desquamated epithelial cells, leukocytes, salivary sediment, food debris and various types of microorganisms.

As the mature calculus develops, it becomes visibly white or yellowish in color unless stained or discolored by some extraneous agency. In addition to being unsightly and undesirable from an aesthetic standpoint, the mature calculus deposits are constant sources of irritation of the gingiva and thereby are a contributing factor to gingivitis and other diseases of the supporting structures of the teeth, the irritation decreasing the resistance of tissues to endogenous and exogenous organisms.

A wide variety of chemical and biological agents have been suggested in the art to retard calculus formation or to remove calculus after it is formed. Mechanical removal of this material periodically by the dentist is, of course, routine dental ofiice procedure.

The chemical approach to calculus inhibition generally involves chelation of calcium ion which prevents the calculus from forming and/ or breaks down mature calculus by removing calcium. A number of chelating agents have been employed for this purpose. See, for example, British Pat. 490,384, granted Feb. 15, 1937, which discloses oral compositions containing ethylenediaminetetraacetic acid, nitrilotriacetic acid and related compounds as anticalculus agents; German Auslegeschrift 1,149,138, published May 22, 1963, which discloses certain water-soluble diglycolates as anticalculus agents; and US. Pat. 1,516,206 which discloses oral compositions containing various sugar lactones for this purpose.

Although certain of the art-disclosed chelators are purportedly safe for use on dental enamel, the chemical similarity of calculus to the tooth structure limits the usefulness of the chelation approach since the more ef- United States Patent fective chelators can seriously damage the tooth structure by decalcification. Thus, the development of oral compositions which elfectively retard calculus by calcium chelation has been impeded by safety considerations.

SUMMARY OF THE INVENTION It has now been discovered that certain carboxyphosphonates possess the surprising capacity to retard the development of dental calculus without removing calcium from dental enamel or otherwise damaging the tooth structure when employed in oral compositions maintained within defined pH limits.

Unlike inorganic polyphosphates such as pyrophosphates, the carboxyphosphonates employed in the compositions of this invention resist hydrolysis in aqueous products and therefore remain in an active form throughout the normal shelf-life of such products.

It is therefore an object of this invention to provide novel oral compositions which retard the formation of calculus without otherwise affecting the tooth structure.

It is another object of this invention to provide an improved method for retarding the development of dental calculus.

Other objects will become apparent from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION This invention is an oral composition effective in inhibiting the formation of dental calculus without adversely affecting the tooth structure comprising (1) from about .01% to about 10% by weight of a carboxyphosphonic acid compound selected from the group consisting of those of the formulae:

(I) coon coon wherein X and Y are each hydrogen and hydroxy, or a pharmaceutically acceptable salt thereof, such as alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., calcium and magnesium), non-toxic heavy metal (e.g., stannous and indium), and ammonium or low molecular weight substituted ammonium (e.g., mono-, di-, and triethanolammonium) salts; and (2) a carrier suitable for use in the oral cavity, the pH of said composition being in the range from about 5.0 to 11.0. The above described carboxyphosphonic acids and their pharmaceutically acceptable salts are referred to collectively hereinafter as carboxyphosphonates.

Operable carboxyphosphonates of the above Formula I include ethane-1,Z-dicarboxy-1,2-diphosphonic acid; ethane-1,2-dicarboxy-l,2 dihydroxy 1,2 diphosphonic acid; ethane-1,2-dicarboxy-1-hydroxy 1,2 diphosphonic acid; and the pharmaceutically acceptable salts of these acids, e.g., sodium, potassium, calcium, magnesium, stannous, indium, ammonium, triethanolammonium, diethanolammonium, and monethanolammonium salts.

Among the operable carboxyphosphonate encompassed by the above Formula II are ethene-1,2-dicarboxyl-phosphonic acid, and the pharmaceutically acceptable salts in this acid, e.g., sodium, potassium, calcium, magnesium, stannous, indium, ammonium, triethanolammonium, diethanolammonium, and monoethanolammonium salts. While the above Formula II is representative of cisisomers, the corresponding trans-isomers are also useful 3 herein. Reference hereinafter to ethene-l,2-dicarboxy-1- phosphonic acid or salts thereof, unless otherwise specified, is intended as contemplating the cisand trans isomers and mixtures thereof.

Mixtures of any of the foregoing carboxyphosphonic acids and/or salts can be used in the practice of this invention.

Ethane 1,2 dicarboxy-1,2-diphosphonic acid and suitable salts thereof can be prepared in any convenient manner. For example, the reaction described by Pudovik in Soviet Research on Organo-Phosphorus Compounds, 1949-1956, Part III, 54785c. can be used to prepare the ester of ethane-1,2-dicarboxy-1,2-diphosphonic acid which in turn can by ordinary hydrolysis reactions be converted to the free acid form. Neutralization by alkali compounds such as sodium hydroxide, potassium hydroxide, alkali carbonates and the like can be used to prepare a desired salt of the acid. A more detailed description of the preparation of these compounds is described in the patent application of D. Allan Nicholson and Darrel Campbell, entitled Built Detergent Compositions, Ser. No. 786,766, filed Dec. 24, 1968, and incorporated herein by reference.

Ethane-1,Z-dicarboxy-1,2-dihydroxy-1,2 diphosphonic acid and related compounds useful herein can be prepared by reaction of an ester of ethane-1,2-dicarboxy-1,2-diphosphonic acid and an alkali metal hypohalite followed by hydrolysis and saponification. This method is more fully described in the patent application of D. Allan Nicholson and Darrel Campbell, entitled Ethane-1,2-Dicarboxy 1,2 Dihydroxy-1,2-Diphosphonic Acid, Lower Alkyl Esters, Alkali Metal Salts Thereof and Process for preparing Same, Ser. No. 786,765, filed Dec. 24, 1968, and incorporated herein by reference.

Ethene-1,2-dicarboxy-l-phosphonic acid and related compounds useful herein can be prepared 'by reaction of an ester of acetylenedicarboxylic acid and a dialkyl phosphite followed by hydrolysis and saponification. This method is more fully described in the patent application of D. Allan Nicholson and Darrel Campbell, entitled Ethane 1,2 Dicarboxy 1 Phosphonic Acid, Esters and Salts Thereof, and Process for Preparing Same, Ser. No. 786,764, filed Dec. 24, 1968, and incorporated herein by reference.

The concentration of carboxyphosphonate in the oral compositions of this invention can range from about .01% to about by weight. Oral compositions which in the ordinary course of usage could be accidentally ingested should contain lower concentrations of carboxyphosphonate. Thus, a mouthwash in accordance with this invention preferably contains less than about 3% by weight of carboxyphosphonate. Dentrifrice compositions, topical solutions and prophylaxis pastes, the latter to be administered professionally, can contain up to about 10% by weight, preferably from about 0.1% to about 5.0% by weight of carboxyphosphonate.

The pH of the composition of this invention can range from about 5.0 to about 11. Below about pH 5.0 damage to the dental enamel can occur in spite of the relative safety of the carboxyphosphonates. Above about pH 11.0 difficulty is encountered in formulating products having satisfactory flavor and mildness. A preferred pH range is from about 7.0 to about 10. The pH of the composition, of course, is determinative of the predominant salt form of the carboxyphosphonates present therein.

While it is not intended that this invention be limited by a particular theory of operation, it has been observed that the carboxyphosphonates encompassed herein interfere with the progress of calculus formation by interfer- I ing with the conversion of amorphous calcium phosphate to crystalline calcium hydroxylapatite. Amounts of carboxyphosphonates which are much too small to chela-te any appreciable quantities of calcium have been found to retard the formation of calcium hydroxylapatite. This selective action on the formative calculus deposits without demineralizing action on the dental enamel is surprising.

The efiicacy of the compositions of this invention in calculus prophylaxis is demonstrated by the Rat Calculus and Crystal Growth Inhibition Tests which are conducted as follows:

RAT CALCULUS STUDY (TOPICAL) Two groups of 20 to 21-day old Holtzman-Sprague- Dawley strain rats, each group comprising one male and one female member of each of 10 litters, are employed in this test, one group serving as the control and the other serving as the test group. Both groups of animals are placed on a calculus inducing diet consisting of 63% cornstarch, 32% non-fat dry milk, 2% liver powder and 3% cellulfiour. Topical applications of a 0.5% aqueous solution of the carboxyphosphonate to be tested, adjusted to pH 10.0, are made on the teeth of each of the animals in the test group for about one minute twice daily, five days per week for three weeks. Similar applications of water are made to each animal in the control group during the experimental period.

Three weeks after the commencement of the test, the animals are sacrificed and their molars are graded for severity of calculus by assessing the area and depth of accumulation on each of the 44 dental surfaces examined in each animal. Grading is made on a 0-3 scale for each surface, 0 being no detectable calcified deposits, 3 being coverage of 50-100% of the surface with a thick deposit and intermediate values representing gradations between these extremes. The total calculus score for each animal is determined by adding the grades for each of the 44 surfaces.

Substantial reductions in calculus formation are attained with topically applied compositions in accordance with this invention.

RAT CALCULUS STUDY (DIETARY) The carboxyphosphonates are also tested for anticalculus activity by including same as components in a calculus inducing diet consisting of 50% cornstarch, 32% non-fat dry milk, 3% liver powder, 5% celluflour, 1% cottonseed oil, 5% powdered sucrose, 1% CaCl -2H O, 2.7% NaH PO -H O and 0.3% MgSO.,. The carboxyphosphonate is included in the diet of the test group of animals. Because the carboxyphosphonates are not appreciably absorbed in the digestive tract at the relatively low concentrations tested, any anticalculus effect observed in this test is due to topical exposure of the dental surfaces to the carboxyphosphonates during ingestion, rather than any systemic effect. This test procedure is conducted in the same manner as the topical study described above, but without topical applications of test solutions and with the change in diet noted above.

Significant reductions in calculus are observed in rats fed a diet containing representative carboxyphosphonates as compared to rats fed an identical diet without carboxyphosphonate.

CRYSTAL GROWTH INHIBITION DETERMINATION As hereinbefore stated, the carboxyphosphonates inhibit the growth of calcium hydroxylapatite crystals and in this way interfere with the normal formation of calcium hydroxylapatite from solution. This test is to determine the effect of the carboxyphosphonates on the calcium phosphate formed on addition of calcium ion to orthophosphate ion at constant pH. The procedure is as follows:

1 ml. of a 0.1 M stock of solution of NaH PO -H O is diluted with 22 ml. of distilled water. 1 ml. of an aqueous solution of the carboxyphosphonate to be tested (at a concentration sufficient to provide the desired ultimate concentration in the reaction mixture) is added to the diluted NaH PO solution and the solution is adjusted to pH 7.4 with sodium hydroxide. To this solution is added 1 ml. of a 0.1 M solution of CaCl -2H O preadjusted to pH 7.4 with sodium hydroxide. This mixture is held at a constant pH 7.4 throughout the reaction period.

After a sufficient reaction time as determined by the operator, generally within 90 minutes, the solution is filtered through a 0.45 millipore filter pad. The precipitate is air-dried and analyzed by X-ray diffraction. The solid calcium phosphate precipitated from the abovedescribed solution without a carboxyphosphonate gives a typical hydroxylapatite pattern, while the calcium phosphate precipitated under the same conditions but in the presence of small amounts of the carboxyphosphonates of this invention is amorphous to X-rays.

Those compounds which are effective in inhibiting the growth of hydroxylapatite crystals at concentrations of less than l.5 l- M under the conditions of this test are found to be elfective in reducing calculus formation.

Table 1 below shows the concentration of various carboxyphosphonates required to inhibit the formation of calcium hydroxylapatite under the conditions specified above.

The presence of the specified amounts of the carboxyphosphonates of Table 1 in the test solutions of the Crystal Growth Inhibition Test results in the precipitation of an amorphous calcium phosphate rather than crystalline calcium hydroxylapatite as occurs without carboxyphosphonate and the total formation of calcium orthophosphate is greatly decreased. By way of comparison, ethylenediaminctetraacetic acid and nitrilotriacetic acid which have been suggested for use as anticalculus agent in the art fail to inhibit crystal growth at molar concentrations of 2.45 l0 respectively. At higher concentrations, these prior art compounds prevent precipitation of calcium phosphate in this test because of their powerful calcium sequestering properties.

A dentifrice, especially toothpaste, containing a carboxyphosphonate is preferred embodiment of this invention. Toothpaste compositions conventionally contain abrasive materials, sudsing agents, binders, humectants, flavoring and sweetening agents.

The abrasive materials and other adjuncts used in the practice of this invention are preferably not sources of much soluble calcium so that the crystal growth in hibiting capacity of carboxyphosphonate is not depleted to an extent that its anticalculus activity is impaired. Thus, conventional abrasives such as dicalcium orthophosphate and calcium carbonate are preferably not used. However, predominantly B-phase calcium pyrophosphate prepared in accordance with the teachings of Schweizer, US. Pat. 3,112,247, granted Nov. 26, 1963, which contains relatively little soluble calcium can be used. An especially preferred class of abrasives for use herein are the particulate thermosetting polymerized resins as described by Cooley et al. in US. Pat. 3,070,510, granted Dec. 25,, 1962. Suitable resins include, for example, melamines, phenolics, ureas, melamine-ureas, melamineformaldehydes, urea-formaldehydes, melamine-ureaformaldehydes, cross-linked epoxides, and cross-linked polyesters.

Other suitable abrasives include alumina and the insoluble non-calcium metaphosphates such as sodium metaphosphate. Mixtures of abrasives can also be used. In any case, the total amount of abrasive in the dentifrice embodiments of this invention can range from 0.5% to 6 by weight of the dentifrice. Preferably, toothpastes contain from 20% to 60% by weight of abrasive. Abrasive particle size preferably ranges from 2 to 2011..

Suitable sudsing agents are those which are reasonably stable and form suds throughout a wide pH range, preferably non-soap anionic organic synthetic detergents. Examples of such. agents are water-soluble salts of alkyl sulfate having from 10 to 18 carbon atoms in the alkyl radical, such as sodium lauryl sulfate; water-soluble salts of sulfonated monoglycerides of fatty acids having from 10 to 18 carbon atoms, such as sodium monoglyceride sulfonates; salts of -C fatty acid amides of taurine, such as sodium N-methyl-N-palmitoyl tauride; salts of C -C fatty acid esters of isethionic acid; and substantially saturated aliphatic acyl amides of saturated mono aminocarboxylic acids having 2 to 6 carbon atoms and in which the acyl radical contains 12 to 16 carbon atoms, such as sodium N-lauroyl sarcoside. Mixtures of two or more sudsing agents can be used.

The sudsing agent can be present in the dentifrice compositions of this invention in an amount from 0.5% to 5% by weight of the total compositions.

In preparing toothpastes, it is necessary to add some thickening material to provide, a desirable consistency. Preferred thickening agents are hydroxyethyl cellulose and water-soluble salts of cellulose ethers such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose. Natural gums such as gum karaya, gum arabic, and gum tragacanth can also be used. Colloidal magnesium aluminum silicate or finely divided silica can be used as part of the thickening agent to further improve texture. Thickening agents in an amount from 0.5% to 5.0% by weight of the total composition can be used.

It is also desirable to include some humectant material in a toothpaste to keep it from hardening. Suitable humectants include glycerine, sorbitol, and other edible polyhydric alcohols. The humectant can comprise up to about 36% by weight of the toothpaste composition.

Suitable flavoring agents include oil of Wintergreen, oil of peppermint, oil of spearmint, oil of sassafras, and oil of clove. Sweetening agents which can be used include saccharin, dextrose, levulose and sodium cyclamate.

Several representative oral compositions illustrating this invention are set forth in the following examples.

EXAMPLE I A toothpaste of the following composition is prepared by conventional methods:

Parts by weight Water 31.58 Sorbitol 6.25

Saccharin 0.12 Calcium pyrophosphate 39.00 Glycerine 18.00 Sodium alkyl (coconut) sulfate 0.40 Sodium coconut monoglyceride sulfonate 0.75 Sodium carboxymethyl cellulose 1.15 Magnesium aluminum silicates 0.40 Flavoring 0.85

Ethane-1,Z-dicarboxy-1,2-diphosphonic acid 1.50

Prepared in accordance with U.S. Pat. 3,112,247 granted Nov. 26, 1963.

This composition effectively retards calculus formation without decalcifying dental enamel.

Toothpaste compositions substantially identical to the composition of Example I are prepared with ethane-1,2- dicarboxy-l,Z-dihydroxy-1,2-diphosphonic acid; ethane- 1,2-dicarboxy-1-hydroxy-1,2-diphosphonic acid; and ethene-1,2-dicarboxy-l-phosphonic acid, respectively, rather than ethane-1,2-dicarboxy-1,2-diphosphonic acid, adjusting the pH to 5.9. These compositions substantially retard calculus formation and do not decalcify dental enamel.

7 EXAMPLE 11 Yet another toothpaste is prepared having the following composition:

Ethane-l,Z-dicarboxy-1,2-dihydroxy-1,2-diphosphonic acid pH5 .3

When employed in the customary manner, this toothd paste retards the formation of dental calculus and no decalcification of dental enamel was observed after seven days exposure.

Several additional toothpastes are prepared having essentially the same composition as the toothpaste of Example II, but using the disodium salt of ethane-1,2-dicarboxy-1,2-diphosphonic acid; the trisodium salt of ethanel,2-dicarboxy-1,2-dihydroxy-l,2-diphosphonic acid; the disodium salt of ethane-1,2-dicarboxy 1 -hydroxy 1,2-diphosphonic acid; the monocalcium salt of ethene-l,2-dicarboxy-l-phosphonic acid; the tetrasodium salt of ethane-1,2-dicarboxy-1,2-diphosphonic acid; the tetrasodium salt of ethene-l,2-dicarboxy-l-phosphonic acid; the monoindium salt of ethane-1,2-dicarboxy-1,2-diphosphonic acid; respectively, rather than ethane-l,2-dicarboxy-l,2- dihydroxy-1,2-diphosphonic acid. The pH of these compositions is adjusted to 7.0. These toothpaste formulations effectively retard calculus formation on dental enamel Without decalcifying same.

Several mouthwash compositions are prepared in accordance with this invention as follows:

Example (parts by weight) Component III IV V VI Glycerine 10. 10. 0 10. 0 10. 0 Ethyl Alcohol 16. 16. 5 16. 5 16. 5 Water 67.172 67. 172 67. 172 70. 192 Tween 80 .12 12 .12 12 Saccharin 045 0. 45 0.45 02 Sodium cyclamate 075 075 075 04 Flavor 088 088 088 088 Carboxyphosphate- 2 3. 0 3 3.0 4 3.0 b 1.0 pH 7. 0 8.5 10. O 10.0

1 Polyoxyethylene moles of ethylene oxide) sorbitan monooleate, a nonionic emulsifier supplied by Atlas Powder Company.

1 Ethane-1, 2-dicarboxy-l, Z-diphosphonic acid.

3 Ethane-1, 2-diearboxy-1, 2-dihydroxy-1, 2-diphosphonio acid.

4 Ethane-1,2-dicarb0xy-1-ph0sphonic acid.

6 Ethane-1, Z-dicarboxy-l-hydroxy-l, 2-diphosphonio acid.

6 Adjusted to value indicated with sodium hydroxide.

When used in the same manner as conventional mouthwash, at least once daily, each of the above compositions materially reduces accumulation of calculus on the surfaces of teeth. No decalcification is observed after several days exposure of dental enamel to these compositions.

Mouthwash compositions corresponding to Example V are prepared, substituting the dimagnesium salt of ethane-1,Z-dicarboxyl,Z-diphosphonic acid; the dipotasslum salt of ethane-1,2-dicarboxy-1,2-dihydroxy 1,2-diphosphonic acid; the monostannous salt of ethane-1,2 dicarboxy-1-hydroxy-1,2-diphosphonic acid; the tetrasodium salt of ethene-1,Z-dicarboxy-l-phosphonic acid and the pentasodium salt of ethane-1,2-dicarboxy-1-hydroxy- 1,2-diphosphonic acid, for the ethene-1,2-dicarboxy-1- phosphonic acid and adjusting the pH to 10.0. These mouthwash compositions retard calculus formation without damaging tooth structure.

8 EXAMPLE VI A prophylaxis paste for use by the dentist for removal of stains and polishing the teeth after mechanical removal of calculus deposits is formulated as follows:

T risodium salt of ethane 1,2 dicarboxy-1,2-diphosphonic acid pH8.0.

When applied to the teeth with a prophylactic rubber cup in the conventional manner, this composition retards the development of new calculus deposits.

The prophylaxis paste set forth above is modified by replacing the trisodium salt of ethane-1,2-dicarboXy-1,2- diphosphonic acid with the trisodium salt of ethane-1,2 dicarboxy-1,Z-dihydroxy-1,2-diphosphonic acid, the trisodium salt of ethene-l,2-dicarboxy-l-phosphonic acid and the trisodium salt of ethane-1,2-dicarboxy-1-hydroxy- 1,2-diphosphonic acid, respectively, with comparable results.

Toothpowders and the like can be prepared by conventional methods and containing, in addition to the usual ingredients, an amount of carboxyphosphonate within the ranges specified herein, to provide an effective means of retarding calculus formation without damaging the tooth structure.

Those components other than carboxyphosphonates which were included in the foregoing examples and various mixtures of those components are illustrative of carriers suitable for use in the oral cavity.

In the reference to pH adjustments in the foregoing examples, it is to be understood that a base of a cation corresponding to the salt form of the carboxyphosphonate employed is used to adjust to higher pH values. In each case in which the carboxyphosphonate was added in its acid form to the example compositions, the pH was adjusted to the specified higher value with NaOH. Adjustments in pH to more acid levels is accomplished with HCl acid. It will be obvious to those skilled in the art that pH adjustments can be made with any acid or base suitable for use in the oral cavity.

What is claimed is:

1. An oral composition effective in inhibiting the formation of dental calculus without adversely affecting tooth structure, comprising (1) from about .01% to about 10% by weight of a carboxyphosphonate selected from the group consisting of those of the formulae:

COOH COOH POQHZ wherein X and Y are each hydrogen and hydroxy, and the pharmaceutically acceptable salts thereof; and (2) a carrier suitable for use in the oral cavity, the pH of the composition being within the range from about 5.0 to about 11.0.

2. The composition of claim 1 wherein the carboxyphosphonate is ethane-1,2-dicarboxy-1,2 diphosphonic acid or a pharmaceutically acceptable salt thereof.

3. The composition of claim 1 wherein the carboxyphosphonate is ethane-1,2-dicarboxy-1,2-dihydroxy-1,2- diphosphonic acid or a pharmaceutically acceptable salt thereof.

4. The composition of claim 1 wherein the carboxy phosphonate is ethene-l,Z-dicarboxy-l-phosphonic acid or a pharmaceutically acceptable salt thereof.

5. A toothpaste composition comprising (1) from about 01% to about 10% by weight of a polyphosphonate selected from the group consisting of those of the formulate:

wherein X and Y are each hydrogen and hydroxy, and the pharmaceutically acceptable salts thereof; and (2) a carrier suitable for use in the oral cavity, the pH of the composition being Within the range from about 5.0 to about 11.0.

6. The composition of claim 5 wherein the carboxyphosphonate is ethane-1,2-dicarboxy-L2 diphosphonic acid or a pharmaceutically acceptable salt thereof.

7. The composition of claim 5 wherein the carboXyphosphonate is ethane-1,Z-dicarboxy-1,2-dihydroxy-1,2-

10 diphosphonic acid or a pharmaceutically acceptable salt thereof.

8. The composition of claim 5 wherein the carboxyphosphonate is ethene-1,Z-dicarboxy-l-phosphonie acid or a pharmaceutically acceptable salt thereof.

References Cited Dental Abstracts, 'vol. 12, No. 9, pp. 539-544, September 1967, 167/93.

Draus et al., Dental Progress, vol. 3, No. 2, pp. 78-81, January 1963, 167/93.

Grossm'an, J. Oral Surg, Oral Med., and Oral Path, vol. 7, pp. 484-487, May 1954, 167/93.

RICHARD L. HUFF, Primary Examiner US. Cl. X.R. 260-502.4; 424-204; 260348 mg UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3553315 Dated January 5, l9l

Marion D. Francis It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2 line 39, "or" should read and Colur line 30, "2.03X should read 2.03Xl0 Column 6 line 12, -C should read C -43 Column 7, in the Table of Examples, change the compone: ."Carboxyphosphate" to read "Carboxyphosphonate" n change "pH" to read pH in Examples IV and V Chang-1 the Saccharin component concentrations from "0.45" to read .045 I Column 8. line. 56, "or" should read and 7 line 59. after "hydrogen" delete "and" and insert or 'the:

Column 9, line 2 "formulate" should read formulae line 4, r" should read and line 8, after hydroge:

"and" should read or Signed and sealed this EOthday' 05-July 1 971 (SEAL) Attest:

EDWARD M.FLETGHER,JR. Attesting Officer- WILLIAM E. SCHUYLER, Commissioner of Pete 

